Intraoral dosage forms of glucagon

ABSTRACT

The present invention provides a composition (e.g., a pharmaceutical composition) comprising at least one delivery agent compound and glucagon. Preferably, the composition includes a therapeutically effective amount of glucagon and the delivery agent compound. The composition of the present invention facilitates the delivery of glucagon and increases its bioavailability compared to administration without the delivery agent compound.

This application is a national phase of International Application No.PCT/US2006/027901, filed Jul. 17, 2006, which claims the benefit of U.S.Provisional Application No. 60/699,617, filed Jul. 15, 2005.International Application No. PCT/US2006/027901 published in English onJan. 25, 2007 under Publication No. WO 2007/011958. These applicationsare incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compositions for delivering glucagoncomponents, including glucagon. Methods for preparation, administrationand treatment are also disclosed.

BACKGROUND OF THE INVENTION

Glucagon, an antihypoglycemic agent (an agent that increases serumglucose concentrations), is a hormone synthesized and secreted by theα-2 cells of the pancreatic islets of Langerhans that increases bloodglucose by stimulating hepatic glyconeogenesis.

Glucagon is a linear peptide of 29 amino acids, and its administrationcauses a rapid rise in blood glucose making it suitable to treat severehypoglycemia.

It is commercially available as a parenteral for injection ofrecombinant DNA origin (Glucagon Diagnostic Kit®, Lilly; GlucagonEmergency Kit®, Lilly; GlucaGen® Diagnostic Kit, Bedford; and mostrecently, GlucaGen HypoKit®, Novo Nordisk A/S). Glucagon is primarilyused for the emergency treatment of severe hypoglycemia if liverglycogen is available (the hyperglycemic response is diminished inconditions associated with starvation, adrenal insufficiency, emaciatedor undernourished patients, or in those with uremia or hepatic disease).It also has utility in the radiographic examination of thegastrointestinal tract (stomach, duodenum, small intestine and colon)where a hypertonic state is advantageous. For this purpose, glucagonappears to be as effective as antimuscarinics and is associated withfewer adverse effects.

Furthermore, there are numerous reports of successful utilization ofglucagon as a cardiac stimulant for the management of cardiacmanifestations of severe beta-blockade overdosage or calcium channelblocker overdossage. These cardiac manifestations, i.e. bradycardia,hypotension, and myocardial depression, have been successfully reversein patients unresponsive to atropine, epinephrine, dopamine, dobutamine,inarrinone, and the like.

These and further uses may be found in AHFS Drug Information, ASHP,Bethseda, Md., 2005, which is incorporated here by reference.

Intraoral (including buccal and sublingual) administration offerssignificant advantages over injectable formulations. Intraoral deliveryreduces hepatic and gastrointestinal first-pass metabolism and canminimize food effect. More importantly, glucagon can be delivered to apatient with severe hypoglycemia by the patient or care provider via theoral mucosa and without the need or training in the delivery of injectedglucagon formulations. Accordingly, there is a need for glucagon dosageforms that can be intraorally administered.

There is also a need for formulations (including oral and intraoralformulations) that have increased bioavailability.

SUMMARY OF THE INVENTION

The present invention provides a composition (e.g., a pharmaceuticalcomposition) comprising at least one delivery agent compound and aglucagon component (e.g. glucagon). Preferably, the composition includesa therapeutically effective amount of a glucagon component and thedelivery agent compound.

In another embodiment of the present invention, the composition is anintraoral dosage form that facilitates the non-parenteral delivery of aglucagon component.

Preferred delivery agent compounds include, but are not limited to,N-(8-[2-hydroxybeinzoyl]amino)caprylic acid (SNAC) andN-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD) and salts thereof,and solvates and hydrates thereof. In a preferred embodiment, the saltis the sodium salt, such as the monosodium salt. In one embodiment, theglucagon component is glucagons and the delivery agent is SNAC.

In one preferred embodiment, the composition comprises a glucagoncomponent and at least one delivery agent of the following structure ora salt thereof:

wherein

-   -   Ar is phenyl or naphthyl;    -   Ar is optionally substituted with one or more of —OH, halogen,        C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;    -   R⁷ is selected from C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl,        naphthyl, (C₁-C₁₀ alkyl) phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀        alkyl) naphthyl, C₂-C₁₀ alkenyl)naphthyl, phenyl (C₁-C₁₀ alkyl),        phenyl (C₂-C₁₀ alkenyl), naphthyl(C₁-C₁₀ alkyl), or        naphthyl(C₂-C₁₀ alkenyl);    -   R⁸ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄        alkoxy, and C₁-C₄ haloalkoxy;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, C¹-C₄alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹, or any combinationthereof;

R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl.

R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof. In some embodiments, the compounds are notsubstituted with an amino group in the position alpha to the acid group.

In another preferred embodiment, the composition comprises a glucagoncomponent (e.g. glucagon), and at least one delivery agent of thefollowing structure or a salt thereof:

wherein

-   -   R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄        alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R⁸, —NO₂, —NR⁹R¹⁰, or        —N⁺R⁹R¹⁰R¹¹(R¹²)⁻;    -   R⁵ is H, —OH, —NO₂, halogen, —CF₃, —NR⁴R⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻,        amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,        carbonate, urea, or —C(O)R¹⁸;    -   R⁵ is optionally substituted with halogen, —OH, —SH, or —COOH;    -   R⁵ is optionally interrupted by O, N, S, or —C(O)—;    -   R⁶ is a C₁-C₁₂ alkylene, C₂-C₁₂ alkenylene, or arylene;    -   R⁶ is optionally substituted with a C₁-C₄ alkyl, C₂-C₄ alkenyl,        C₁-C₄ alkoxy, —OH, —SH, halogen, —NH₂, or —CO₂R⁸;    -   R⁶ is optionally interrupted by O or N;    -   R⁷ is a bond or arylene;    -   R⁷ is optionally substituted with —OH, halogen, —C(O)CH₃,        —NR¹⁰R¹¹, or —N⁺R¹⁰R¹¹R¹²(R¹³)⁻;    -   each occurrence of R⁸ is independently H, C₁-C₄ alkyl, C₂-C₄        alkenyl, or —NH₂;    -   R⁹, R¹⁰, R¹¹, and R¹² independently H or C₁-C₁₀ alkyl;    -   R¹³ is a halide, hydroxide, sulfate, tetrafluoroborate, or        phosphate;    -   R¹⁴, R¹⁵ and R¹⁶ are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl        substituted with —COOH, C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl        substituted with —COOH, or —C(O)R¹⁷;    -   R¹⁷ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl; and    -   R¹⁸ is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵, or N⁺R¹⁴R¹⁵R¹⁶(R¹³).

Optionally, when R¹, R², R³, R⁴, and R⁵ are H, and R⁷ is a bond then R⁶is not a C₁-C₆, C₉ or C₁₀ alkyl.

Optionally, when R¹, R², R³, and R⁴ are H, R⁵ is —OH, R⁷ is a bond thenR⁶ is not a C₁-C₃ alkyl.

Optionally, when at least one of R¹, R², R³, and R⁴ is not H, R⁵ is —OH,R⁷ is a bond, then R⁶ is not a C₁-C₄ alkyl.

Optionally, when R¹, R², and R³ are H, R⁴ is —OCH₃, R⁵ is —C(O)CH₃, andR⁶ is a bond then R⁷ is not a C₃ alkyl.

Optionally, when R¹, R², R⁴, and R¹ are H, R³ is —OH, and R⁷ is a bondthen R⁶ is not a methyl.

In yet another embodiment the composition comprises a glucagon componentand at least one delivery agent of the following structure or a saltthereof:

wherein

R¹, R², R³, R⁴ and R⁵ are independently H, —CN, —OH, —OCH₃, or halogen,at least one of R¹, R², R³, R⁴ and R⁵ being —CN; and

R⁶ is a C₁-C₁₂ linear or branched alkylene, alkenylene, arylene,alkyl(arylene) or aryl(alkylene).

According to one embodiment, when R¹ is —CN, R⁴ is H or —CN, and R², R³,and R⁵ are H, then R⁶ is not methylene ((CH₂)₁).

Also provided is a dosage unit form (e.g., an oral or intraoral dosageunit form) comprising the composition of the present invention. Thedosage unit form may be in the form of a liquid or a solid, such as atablet, capsule or particle, including a powder or sachet, and ispreferable an intraoral dosage form.

Another embodiment is a method for administering glucagon to an animalin need thereof, by administering the composition or dosage unit form(s)of the present invention to the animal. The preferred route ofadministration is oral or intraoral.

Yet another embodiment is a method of treating hypoglycemia in an animal(such as a human) in need thereof by administering an effective amountof the composition of the present invention to the animal.

Yet another embodiment is a method for treating conditions or disorderswhich can be alleviated by administering to an animal (such as a human)a therapeutically effective amount of the composition or dosage unitform(s) of the present invention. Such conditions and disorders, includebut are not limited to, hypoglycemia, hypoglycemia associated withexcess insulin administration (e.g. insulin coma) hypoglycemiaassociated with excess administration of any antidiabetic medication,the radiographic examination of the gastrointestinal tract, or to treatsevere cardiac manifestations (e.g. bradycardia, hypotension, myocardialdepression) associated with overdosage of beta-adrenergic blockers orcalcium channel blockers.

Yet another embodiment is a method of preparing a composition of thepresent invention by mixing at least one delivery agent compound and aglucagon component (e.g. glucagon).

Yet another embodiment is a dosage unit form for intraoraladministration comprising at least one delivery agent compound and aglucagon component (e.g. glucagon). The dosage unit form may be, forexample, in the form of a solid, such as a tablet or candy whichdissolves in the mouth, a powder, a liquid, or a thin sheet, or anyother form which dissolves and/or sticks to the interior of the mouth,or facilitates the intraoral administration of glucagon.

Yet another embodiment is a method for treating conditions or disorderswhich can be alleviated by reducing nutrient availability in an animal(such as a human) by intraorally administering to the animal atherapeutically effective amount of the composition or dosage unitform(s) of the present invention. Such conditions and disorders, includebut are not limited to, those described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of serum glucose concentrations in beagles versus timeafter intraoral administration of 1 mg/kg of glucagon and 100 mg/kg ofSNAC compared to the same dose of oral solution of glucagon and SNAC.

FIG. 2 is a graph of serum glucose concentrations in beagles versus timeafter sublingual administration of a tablet containing 1 mg of glucagonand 20 mg manitol compared with intramuscular administration of glucagon0.15 mg.

FIG. 3 is a graph of serum glucose concentrations in a beagle versustime after intraoral administration of 0.3 mg/kg of glucagon and 30 mgof SNAC.

FIGS. 4 and 5 are graphs of serum glucose concentrations in a beagleversus time in a dose response study.

FIGS. 6 and 7 are graphs of serum glucose concentrations in a beagleversus time in a study comparing gel, lyophilization, air-dryed andphysical blending formulation techniques.

FIG. 8 is a graph of serum glucose concentrations in beagles versus timeafter intraoral administration of 0.3 mg/kg of glucagon and 100 mg/kg ofSNAC.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention may comprise dosage unit forms forintraoral administration comprising (a) at least one glucagon, aglucagon agonist, or a mixture thereof, and (b) a delivery agent of theformula:

and salts thereof, wherein:

Ar is phenyl or naphthyl;

Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

R⁷ is selected from C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl,(C₁-C₁₀ alkyl) phenyl, C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl,(C₂-₁₀alkenyl)naphthyl, phenyl (C₁-C₁₀ alkyl), phenyl (C₂-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl);

R⁸ is selected from hydrogen, C₁-C₄ alkyl, to C₂-C₄ alkenyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₂ -C₄ alkenyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹, or any combinationthereof;

R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; and

R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof. In some embodiments, the compounds are notsubstituted with an amino group in the position alpha to the acid group.

Embodiments of the invention may comprise dosage unit forms forintraoral administration comprising (a) at least one glucagon componentand (b) a delivery agent of the formula

and salts thereof, wherein

-   -   R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄        alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R⁸, —NO₂, —N⁺R⁹R¹⁰, or        —N⁺R⁹R¹⁰R¹¹(R¹²)⁻;    -   R⁵ is H, —OH, —NO₂, halogen, —CF₃, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻,        amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,        carbonate, urea, or —C(O)¹⁸;    -   R⁵ is optionally substituted with halogen, —OH, —SH, or —COOH;    -   R⁵ is optionally interrupted by O, N, S, or —C(O)—;    -   R⁶ is a C₁-C₁₂ alkylene, C₂-C₁₂ alkenylene, or arylene;    -   R⁶ is optionally substituted with a C₁-C₄ alkyl, C₂-C₄ alkenyl,        C₁-C₄ alkoxy, —OH, —SH, halogen, —NH₂, or —CO₂R⁸;    -   R⁶ is optionally interrupted by O or N;    -   R⁷ is a bond or arylene;    -   R⁷ is optionally substituted with —OH, halogen, —C(O)CH₃,        —NR¹⁰R¹¹, or —N+R¹⁰R¹¹R¹²(R¹³)⁻;    -   R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or —NH₂;    -   R⁹, R¹⁰, R¹¹, and R¹² independently H or C₁-C₁₀ alkyl;    -   R¹³ is a halide, hydroxide, sulfate, tetrafluoroborate, or        phosphate; and    -   R¹⁴, R¹⁵ and R¹⁶ are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl        substituted with —COOH, C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl        substituted with —COOH, —C(O)R¹⁷;    -   R¹⁷ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl; and    -   R¹⁸ is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵, or N⁺R¹⁴R¹⁵R¹⁶(R¹³).

Embodiments of the invention may comprise dosage unit forms forintraoral administration comprising a glucagon component (e.g. glucagonor a glucagon agonist) and a delivery agent of the formula

and salts thereof, wherein

-   -   R¹, R², R³, R⁴ and R⁵ are independently H, —CN, —OH, —OCH₃, or        halogen, at least one of R¹, R², R³, R⁴ and R⁵ being —CN; and    -   R⁶ is C₁-C₁₂ linear or branched alkylene, alkenylene, arylene,        alkyl(arylene) or aryl(alkylene).

Embodiments of the invention may comprise a delivery agent selected fromthe group comprising the monosodium salt ofN-(8-[2-hydroxybenzoyl]-amino)caprylic acid, the monosodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the monosodium salt of8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, the monosodium salt of8-(2,6-dihydroxybenzoylamino)octanoic acid, the monosodium salt of8-(2-hydroxy-5-bromobenzoylamino)octanoic acid, the monosodium salt8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid, the monosodium salt of8-(2-hydroxy-5-iodobenzoylamino)octanoic acid, the monosodium salt of8-(2-hydroxy-5-methylbenzoylamino)octanoic acid, the monosodium salt of8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid, the monosodium salt of8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid, the monosodium salt of8-(3-hydroxyphenoxy)octanoic acid, the monosodium salt of8-(4-hydroxyphenoxy)octanoic acid, the monosodium salt of6-(2-cyanophenoxy)hexanoic acid, the monosodium salt of8-(2-Hydroxyphenoxy)octyl-diethanolamine, disodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the disodium salt of8-(4-hydroxyphenoxy)octanoate, the monosodium salt of8-(4-hydroxyphenoxy)octanoate, the disodium salt of8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, and the disodium saltof 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid.

Embodiments of the invention may comprise a delivery agentN-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceuticallyacceptable salt thereof, or N-(10-[2-hydroxybenzoyl]-amino)decanoic acidor a pharmaceutically acceptable salt thereof.

Embodiments of the invention may comprise any dosage unit form describedabove with an excipient, a diluent, a disintegrant, a lubricant, aplasticizer, a colorant, a dosing vehicle, or any combination thereof.

Embodiments of the invention may comprise dosage unit forms in the formof, e.g., a tablet, a capsule, a particle, a powder, a sachet, or aliquid.

Embodiments of the invention may comprise a dosing vehicle which is aliquid selected from the group comprising, e.g., water, aqueouspropylene glycol, phosphate buffer, 1,2-propane diol, ethanol, Klucel®or any combination thereof.

Embodiments of the invention may comprise methods for administering aneffective amount of glucagon, a glucagon agonist or a combinationthereof, to a patient in need thereof, comprising the step ofintraorally administering any of the dosage unit forms described above.The glucagon may be combined with the delivery agent, e.g.,N-(8-[2-hydroxybenzoyl]amino)caprylic acid orN-(10-[2-hydroxybenzoyl]-amino)decanoic acid or a pharmaceuticallyacceptable salt thereof.

Embodiments of the invention may comprise methods of treatinghypoglycemia in a patient in need thereof, comprising the step ofadministering to the patient an effective amount of any of the dosageunit forms described above.

Embodiments of the invention may comprise methods of treating acondition or disorder that may be alleviated by reducing nutrientavailability in a patient in need thereof, comprising the step ofadministering to an animal an effective amount of any of the dosage unitforms described above. The condition or disorder may, e.g., be selectedfrom the group comprising hypoglycemia, bradycardia, hypotension, andmyocardial depression or any combination thereof.

Embodiments of the invention may comprise methods of improving thebioavailability of glucagon or in an animal, the method comprising thestep of administering any of the dosage unit forms described above.

Embodiments of the invention may comprise methods of preparing a dosageunit form comprising the step of mixing of glucagon and a delivery agentof the formula:

or a salt thereof, wherein:

Ar is phenyl or naphthyl;

Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

R⁷ is selected from C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl,(C₁-C₁₀ alkyl) phenyl, C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl,C₂-C₁₀ alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl);

R⁸ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy,and C₁-C₄ haloalkoxy;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹, or any combinationthereof;

R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; and R⁷ is optionallyinterrupted by oxygen, nitrogen, sulfur or any combination thereof.

Definitions

The term “glucagon component” refers to all forms of glucagon,including, but not limited to naturally occurring glucagon, glucagonproduced by recombinant DNA technology, or glucagon produced by orderived from any other means. Glucagon components also includefragments, agonists, and analogs of glucagon which have the same orsimilar pharmacological activity as glucagon.

The term “hydrate” as used herein includes, but is not limited to, (i) asubstance containing water combined in the molecular form and (ii) acrystalline substance containing one or more molecules of water ofcrystallization or a crystalline material containing free water.

The term “solvate” as used herein includes, but is not limited to, amolecular or ionic complex of molecules or ions of a solvent withmolecules or ions of the delivery agent compound or salt thereof, orhydrate or solvate thereof.

The term “delivery agent” refers to any of the delivery agent compoundsdisclosed herein.

The term “SNAC” refers to the monosodium salt ofN-(8-[2-hydroxybenzoyl]-amino)caprylic acid.

The term “SNAD” refers to the monosodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid. The term “disodium salt ofSNAD” refers to the disodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid.

An “effective amount of glucagon” is an amount of glucagon which iseffective to treat or prevent a condition in a living organism to whomit is administered over some period of time, e.g., provides atherapeutic effect during a desired dosing interval.

An “effective amount of delivery agent” is an amount of the deliveryagent which enables and/or facilitates the absorption of a desiredamount of glucagon via any route of administration (such as thosediscussed in this application including, but not limited to, the oral(e.g., across a biological membrane in the gastrointestinal tract),nasal, pulmonary, dermal, intraoral, vaginal, and/or ocular route).

The term “AUC” as used herein, means area under the plasmaconcentration-time curve, as calculated by the trapezoidal rule over thecomplete dosing interval, e.g., 24-hour interval.

The term “mean”, when preceding a pharmacokinetic value (e.g., meanPeak) represents the arithmetic mean value of the pharmacokinetic valueunless otherwise specified.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the,” include plural referents unless the context clearly indicatesotherwise. Thus, for example, reference to “a molecule” includes one ormore of such molecules, “a reagent” includes one or more of suchdifferent reagents, reference to “an antibody” includes one or more ofsuch different antibodies, and reference to “the method” includesreference to equivalent steps and methods known to those of ordinaryskill in the art that could be modified or substituted for the methodsdescribed herein.

The term “about” generally means within 10%, preferably within 5%, andmore preferably within 1% of a given value or range.

The terms “alkyl” and “alkenyl” as used herein include linear andbranched alkyl and alkenyl substituents, respectively.

The term “patient” as used herein refers to a mammal and preferably ahuman.

The phrase “pharmaceutically acceptable” refers to additives orcompositions that are physiologically tolerable when administered to amammal.

The terms “intraoral administration” and “intraorally administering”include administration by adsorption through any surface inside themouth or upper throat (such as the cheek (e.g., the inner cheek lining),gums, palate, tongue, tonsils, periodontal tissue, lips, and the mucosaof the mouth and pharynx). These terms, for example, include sublingualand buccal administration.

Delivery Agent Compounds

The delivery agent compound may be any of those described in U.S. Pat.Nos. 5,650,386 and 5,866,536 and International Publication Nos.WO94/23767, WO95/11690, WO95/28920, WO95/28838, WO96/10396, WO96/09813,WO96/12473, WO96/12475, WO96/30036, WO96/33699, WO97/31938, WO97/36480,WO98/21951, WO98/25589, WO98/34632, WO98/49135, WO99/16427, WO00/06534,WO00/07979, WO00/40203, WO00/46182, WO00/47188, WO00/48589, WO00/50386,WO00/59863, WO00/59480, WO01/32130, WO01/32596, WO01/34114, WO01/44199,WO01/51454, WO01/70219, WO01/92206, WO02/02509, WO02/15959, WO02/16309,WO02/20466, WO02/19969, WO02/070438, WO03/026582, WO02/100338,WO03/045306, and WO0326582, all of which are hereby incorporated byreference.

Non-limiting examples of delivery agent compounds includeN-(8-[2-hydroxybenzoyl]-amino)caprylic acid,N-(10-[2-hydroxybenzoyl]-amino)decanoic acid,8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,8-(2,6-dihydroxybenzoylamino)octanoic acid,8-(2-hydroxy-5-bromobenzoylamino)octanoic acid,8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,8-(2-hydroxy-5-iodobenzoylamino)octanoic acid,8-(2-hydroxy-5-methylbenzoylamino)octanoic acid,8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid,8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid,8-(3-hydroxyphenoxy)octanoic acid, 8-(4-hydroxyphenoxy)octanoic acid,6-(2-cyanophenoxy)hexanoic acid,8-(2-Hydroxyphenoxy)octyl-diethanolamine, 8-(4-hydroxyphenoxy)octanoate,8-(4-hydroxyphenoxy)octanoate,8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid, and salts thereof.Preferred salts include, but are not limited to, monosodium and disodiumsalts.

The delivery agent compounds may be in the form of the carboxylic acidor pharmaceutically acceptable salts thereof, such as sodium salts, andhydrates and solvates thereof. The salts may be mono- or multi-valentsalts, such as monosodium salts and disodium salts. The delivery agentcompounds may contain different counter ions chosen for example due totheir effect on modifying the dissolution profile of the carrier.

The delivery agent compounds may be prepared by methods known in theart, such as those discussed in the aforementioned publications (e.g.,International Publication Nos. WO 98/34632, WO 00/07979, WO 01/44199, WO01/32596, WO 02/20466, and WO 03/045306). SNAC, SNAD, and the free acidand other salts thereof may be prepared by any method known in the art,such as those described in U.S. Pat. Nos. 5,650,386 and 5,866,536.

The delivery agent compound may be selected from the followingcompounds, and pharmaceutically acceptable salts thereof:2-HO—Ar—C(O)—NR⁸—R⁷—COOH  Formula (1)wherein

Ar is phenyl or naphthyl, optionally substituted with OH, halogen, C₁-C₄alkyl, C₁-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

R⁷ is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀alkyl)phenyl, (C₁-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₁-C₁₀alkenyl) naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₁-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₁-C₁₀ alkenyl);

R⁸ is hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁ to C₄ alkoxy, C₁-C₄or haloalkoxy;

R⁷ is optionally substituted with C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁to C₄ alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹ or any combinationthereof;

R⁹ is hydrogen, C₁ to C₄ alkyl or C₂ to C₄ alkenyl; and

R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof; with the proviso that the compounds are notsubstituted with an amino group in the position alpha to the acid group;2-OH—Ar—C(O)—NH—R¹—R²  Formula (2)wherein

Ar is phenyl or naphthyl;

Ar is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, aryloxy, a heterocyclic ring, C₅-C₇carbocylic ring, halogen, —OH, —SH, CO₂R⁶, —NR⁷R⁸, or —N⁺R⁷R⁸R⁹Y⁻;

(a) R¹ is C₁-C₁₆ alkylene, C₂-C₁₆ alkenylene, C₂-C₁₆ alkynylene, C₆-C₁₆arylene, (C₁-C₁₆ allyl)arylene, or aryl (C₁-C₁₆ alkylene);

-   -   R² is —NR³R⁴ or —N⁺R³R⁴R⁵Y⁻;    -   R³ and R⁴ are independently hydrogen; oxygen; hydroxy;        substituted or unsubstituted C₁-C₁₆ alkyl; substituted or        unsubstituted C₂-C₁₆ alkenyl; substituted or unsubstituted        C₂-C₁₆ alkynyl; substituted or unsubstituted aryl; substituted        or unsubstituted alkylcarbonyl; substituted or unsubstituted        arylcarbonyl; substituted or unsubstituted alkanesulfinyl;        substituted or unsubstituted arylsulfinyl; substituted or        unsubstituted alkanesulfonyl; substituted or unsubstituted        arylsulfonyl; substituted or unsubstituted alkoxycarbonyl;        substituted or unsubstituted aryloxycarbonyl;    -   R⁵ is independently hydrogen; substituted or unsubstituted        C₁-C₁₆ alkyl; substituted or unsubstituted C₂-C₁₆ alkenyl;        substituted or unsubstituted C₂-C₁₆ alkynyl; substituted or        unsubstituted aryl; substituted or unsubstituted alkylcarbonyl;        substituted or unsubstituted arylcarbonyl; substituted or        unsubstituted alkanesulfinyl; substituted or unsubstituted        arylsulfinyl; substituted or unsubstituted alkanesulfonyl;        substituted or unsubstituted arylsulfonyl; substituted or        unsubstituted alkoxycarbonyl; substituted or unsubstituted        aryloxycarbonyl;

(b) R¹, R², and R⁵ are as defined above; and

-   -   R³ and R⁴ are combined to form a 5, 6 or 7-membered heterocyclic        ring; or 5, 6 or 7-membered heterocyclic ring substituted with a        C₁-C₆ alkyl, C₁-C₆ alkoxy, aryl, aryloxy, oxo group or        carbocyclic ring; or

(c) R² and R⁵ are as defined above; and

-   -   R¹ and R³ are combined to form a 5, 6 or 7-membered heterocyclic        ring; or 5, 6 or 7-membered heterocyclic ring substituted with a        C₁-C₆ allyl, alkoxy, aryl, aryloxy, or oxo group or carbocyclic        ring;    -   R⁴ is hydrogen; oxygen; hydroxy; substituted or unsubstituted        C₁-C₁₆ alkyl; substituted or unsubstituted C₂-C₁₆ alkenyl;        substituted or unsubstituted C₂-C₁₆ alkynyl; substituted or        unsubstituted aryl; substituted or unsubstituted alkylcarbonyl;        substituted or unsubstituted arylcarbonyl; substituted or        unsubstituted alkanesulfinyl; substituted or unsubstituted        arylsulfinyl; substituted or unsubstituted alkanesulfonyl;        substituted or unsubstituted arylsulfonyl; substituted or        unsubstituted alkoxycarbonyl; substituted or unsubstituted        aryloxycarbonyl;

R⁶ is hydrogen; C₁-C₄ alkyl; C₁-C₄ alkyl substituted halogen or —OH;C₂-C₄ alkenyl; or C₂-C₄ alkenyl substituted halogen or —OH;

R⁷, R⁸, and R⁹ are independently hydrogen; oxygen; C₁-C₄ alkyl; C₁-C₄alkyl substituted with halogen or —OH; C₂-C₄ alkenyl; or C₂-C₄ alkenylsubstituted with halogen or —OH; and

Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy,perchlorate, tetrafluoroborate, or carboxylate;

wherein

R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷, halogen,C₁-C₄ alkyl, or C₁-C₄ alkoxy;

R⁵ is a substituted or unsubstituted C₂-C₁₆ alkylene, substituted orunsubstituted C₂-C₁₆ alklenylene, substituted or unsubstituted C₁-C₁₂alkyl(arylene), or substituted or unsubstituted aryl(C₁-C₁₂ alkylene);and

R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;

wherein

(a) R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl,C₁-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R⁸, —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹¹(Y⁻);

-   -   R⁸ is hydrogen, —OH, C₁-C₆ alkyl, C₁-C₄ alkyl substituted with        halogen or —OH, C₂-C₄ alkenyl unsubstituted or substituted with        halogen or —OH, or —NR¹⁴R¹⁵;    -   R⁹, R¹⁰, and R¹¹ are independently hydrogen, oxygen, C₁-C₄ alkyl        unsubstituted or substituted with halogen or —OH, C₂-C₄ alkenyl        unsubstituted or substituted with halogen or —OH;    -   Y is halide, hydroxide, sulfate, nitrate, phosphate, alkoxy,        perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate,        malonate, succinate, tartrate, acetate, gluconate, maleate;    -   R⁵ is H, —OH, —NO₂, halogen, CF₃, —NR⁴R⁵, —N⁺R¹⁴R¹⁵R¹⁶(Y⁻),        amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,        carbonate, urea, or —C(O)R²²; R⁵ is optionally substituted with        halogen, —OH, —SH, or —COOH; R⁵ is optionally interrupted by O,        N, S, or —C(O)—;    -   R⁴, R¹⁵, and R¹⁶ are independently H or C₁-C₁₀ alkyl;    -   R²² is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵;    -   R⁶ is substituted or unsubstituted C₁-C₁₆ alkylene, C₂-C₁₆        alkenylene, C₂-C₁₆ alkynylene, C₅-C₁₆ arylene, (C₁-C₁₆ alkyl)        arylene or aryl(C₁-C₁₆ alkylene); R⁶ is optionally substituted        with C₁-C₇ alkyl or C₁-C₇ cycloalkyl;    -   R⁷ is —NR¹⁵R¹⁹ or —N⁺R¹⁸R¹⁹R²⁰Y⁻;    -   R¹⁸ and R¹⁹ are independently hydrogen, oxygen, hydroxy,        substituted or unsubstituted C₁-C₁₆ alkyl, substituted or        unsubstituted C₂-C₁₆ alkenyl, substituted or unsubstituted        C₂-C₁₆ alkynyl, substituted or unsubstituted aryl, substituted        or unsubstituted alkylcarbonyl (e.g. substituted or        unsubstituted (C₁₋₆ alkyl)carbonyl), substituted or        unsubstituted arylcarbonyl, substituted or unsubstituted        alkanesulfinyl (e.g. substituted or unsubstituted (C₁₋₆        alkane)sulfinyl), substituted or unsubstituted arylsulfinyl,        substituted or unsubstituted alkanesulfonyl (e.g. substituted or        unsubstituted (C₁₋₆ alkane)sulfonyl), substituted or        unsubstituted arylsulfonyl, substituted or unsubstituted        alkoxycarbonyl (e.g. substituted or unsubstituted (C₁₋₆        alkoxy)carbonyl), or substituted or unsubstituted        aryloxycarbonyl, or substituted or unsubstituted C₅-C₇        heterocyclic ring (i.e., 5, 6, or 7-membered heterocyclic ring),        wherein the substitutions may be halogen or —OH; and    -   R²⁰ is independently hydrogen, substituted or unsubstituted        C₁-C₁₆ alkyl, substituted or unsubstituted C₂-C₁₆ alkenyl,        substituted or unsubstituted C₂-C₁₆ alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkylcarbonyl        (e.g. substituted or unsubstituted (C₁₋₆ alkyl)carbonyl),        substituted or unsubstituted arylcarbonyl, substituted or        unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted        (C₁₋₆ alkane)sulfinyl), substituted or unsubstituted        arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g.        substituted or unsubstituted (C₁₋₆ alkane)sulfonyl), substituted        or unsubstituted arylsulfonyl, substituted or unsubstituted        alkoxycarbonyl (e.g. substituted or unsubstituted (C₁₋₆        alkoxy)carbonyl), or substituted or unsubstituted        aryloxycarbonyl; or

(b) R¹-R¹⁶ and R²⁰ are as defined above; and

-   -   R¹⁸ and R¹⁹ combine to form a 5, 6, or 7-membered heterocyclic        ring optionally interrupted with an oxo group and unsubstituted        or substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, aryl, aryloxy, or        carbocyclic ring;

wherein

R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, —C(O)R⁸, —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹¹(R²)⁻;

R⁵ is H, —OH, —NO₂, halogen, —CF₃, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide,C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate, carbonate, urea,or —C(O)R¹⁸;

R⁵ is optionally substituted with halogen, —OH, —SH, or —COOH;

R⁵ is optionally interrupted by O, N, S, or —C(O)—;

R⁶ is a C₁-C₁₂ alkylene, C₂-C₁₂ alkenylene, or arylene;

R⁶ is optionally substituted with a C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄alkoxy, —OH, —SH, halogen, —NH₂, or —CO₂R⁸;

R⁶ is optionally interrupted by O or N;

R⁷ is a bond or arylene;

R⁷ is optionally substituted with —OH, halogen, —C(O)CH₃, —NR¹⁰R¹¹, or—N⁺R¹⁰R¹¹R¹²(R¹³)⁻;

R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or —NH₂;

R⁹, R¹⁰, R¹¹, and R¹² independently H or C₁-C₁₀ alkyl;

R¹³ is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;and

R¹⁴, R¹⁵ and R¹⁶ are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylsubstituted with —COOH, C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with—COOH, —C(O)R¹⁷;

R¹⁷ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl; and

R¹⁸ is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵, or N¹⁴R¹⁵R¹⁶(R¹³); and

wherein

R¹, R², R³, and R⁴ are independently H, —OH, halogen, —OCH₃, —NR¹⁰R¹¹ or—N⁺R¹⁰R¹¹R¹²(R¹³)⁻;

R⁵ is H, —OH, —NO₂, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide, C₁-C₁₂ alkoxy,C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate, carbonate, urea, or —C(O)R¹⁸;

R⁵ is optionally substituted with —OH, —SH, or —COOH;

R⁵ is optionally interrupted by O, N, S, or —C(O)⁻;

R⁶ is a C₁-C₁₂ alkylene, C₁-C₁₂ alkenylene, or arylene;

R⁶ is optionally substituted with a C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄alkoxy, —OH, —SH, halogen, —NH₂, or —CO₂R⁹;

R⁶ is optionally interrupted by O or N;

R⁷ is a bond or arylene;

R⁷ is optionally substituted with —OH, halogen, —C(O)CH₃, —NR¹⁰R¹¹ or—N⁺R¹⁰R¹¹R¹²(R¹³)⁻;

R⁸ is H or C₁-C₄ alkyl;

R⁹ is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;

R¹⁰, R¹¹, and R¹² are independently H or C₁-C₁₀ alkyl;

R¹³ is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;

R¹⁴, R¹⁵, and R¹⁶ are independently H, C₁-C₁₀ alkyl, C₂-C₁₂ alkenyl, 0,or —C(O)R¹⁷;

R¹⁷ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl; and

R¹⁸ is —OH, C₁-C₆ alkyl, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻; and

wherein

R¹⁹ is —NO₂ or —C(O)R²³;

R²⁰ is a C₁-C₁₂ alkylene or C₁-C₁₂ alkenylene;

R¹¹ is a bond or arylene;

R²² is H or C₁-C₄ alkyl; and

R¹³ is —OH, C₁-C₆ alkyl, or —NH₂.

Salts of the delivery agent compounds of the present invention may beprepared by methods known in the art. For example, sodium salts may beprepared by dissolving the delivery agent compound in ethanol and addingaqueous sodium hydroxide.

The delivery agent compound may be purified by recrystallization or byfractionation on one or more solid chromatographic supports, alone orlinked in tandem. Suitable recrystallization solvent systems include,but are not limited to, acetonitrile, methanol, and tetrahydrofuran.Fractionation may be performed on a suitable chromatographic supportsuch as alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase chromatography using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater or an appropriate buffer as the mobile phase. When anion exchangechromatography is performed, preferably a 0-500 mM sodium chloridegradient is employed.

Delivery Systems

The composition of the present invention comprises one or more deliveryagent compounds of the present invention and a glucagon component. Thedelivery agent compound and glucagon component are typically mixed priorto administration to form an administration composition.

The administration compositions may be in the form of a liquid. Thesolution medium may comprise dosing vehicles such as, e.g., water, 25%aqueous propylene glycol, or phosphate buffer. Other dosing vehiclesinclude polyethylene glycol or Klucel. Dosing solutions may be preparedby mixing a solution of the delivery agent compound with a solution ofthe active agent, just prior to administration. Alternately, a solutionof the delivery agent compound (or glucagon) may be mixed with the solidform of glucagon (or delivery agent compound). The delivery agentcompound and glucagon may also be mixed as dry powders. The deliveryagent compound and glucagon thereof can also be admixed during themanufacturing process.

The dosing solutions may optionally contain additives such as phosphatebuffer salts, citric acid, glycols, or other dispersing agents.Stabilizing additives may be incorporated into the solution, preferablyat a concentration ranging between about 0.1 and about 20% (w/v).

The administration compositions may alternately be in the form of asolid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by manually or physicallyblending the solid form of the delivery agent compound with the solidform of glucagon. Alternately, a solid may be obtained from a solutionof the delivery agent compound and glucagon by methods known in the art,such as freeze-drying (lyophilization), precipitation, crystallization,air drying and solid dispersion. Techniques for obtaining active agents(i.e. glucagon) and delivery agents from a solution are disclosed inInternational Application No. PCT/US03/15629, and U.S. Ser. No.11/204,756 and 11/204,778 (see, e.g., Example 1). The glucagon and/ordelivery agent compound may also be in micronized form, as described inU.S. Ser. No. 11/204,756 and 11/204,778. Each of these applications arehereby incorporated by reference in their entirety.

In one embodiment of the present invention the glucagon/delivery agentcomposition for tableting is prepared by dissolving a glucagon componentand the delivery agent in a solvent (e.g. de-ionized water) andrecovering the solid from the solution by lyophilization. In oneembodiment of the present invention the a glucagon/delivery agentcomposition for tableting is prepared by dissolving glucagon and thedelivery agent in a solvent (e.g. de-ionized water) and recovering thesolid from the solution by air drying.

Alternatively, the administration can be a semi-solid, in the form of agel, paste, colloid, gelatin, emulsion, suspension and the like.

The administration compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. Other enzyme inhibitors include, but are notlimited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

The amount of glucagon component used in an administration compositionof the present invention is an amount effective to treat the targetindication. However, the amount can be less than that amount when thecomposition is used in a dosage unit form because the dosage unit formmay contain a plurality of delivery agent compound glucagon agonistcompositions or may contain a divided effective amount. The totaleffective amount can then be administered in cumulative unitscontaining, in total, an effective amount of a glucagon component.Moreover, those skilled in the filed will recognize that an effectiveamount of glucagon component will vary with many factors including theage and weight of the patient, the patient's physical condition, theblood sugar level, the weight level to be obtained, as well as otherfactors.

The total amount to be used of glucagon component can be determined bymethods known to those skilled in the art. However, because thecompositions of the invention may deliver a glucagon component moreefficiently than compositions containing glucagon component alone, loweramounts of glucagon component than those used in prior dosage unit formsor delivery systems can be administered to the subject, while stillachieving the same blood levels and/or therapeutic effects.

According to one embodiment the amount of glucagon componentadministered with the delivery agent is an amount sufficient to raiseserum glucose to a desired level. In one embodiment, the effective doseof glucagon component (e.g. glucagon) generally ranges from about 1 mgto about 5 mg per dose. Preferably the dosage forms of the presentinvention contains from about 0.25 mg/kg to about 2 mg/kg/dose of theglucagon component.

The present invention also includes pharmaceutical compositions anddosage forms which include the aforementioned amounts of glucagoncomponent and at least one delivery agent.

Generally an effective amount of delivery agent to facilitate thedelivery of a glucagon component is administered with the glucagoncomponent. Generally the amount of delivery agent to glucagon component,on a molar basis, ranges from about 25000:1 to about 50:1 or 1:1 orless, preferably from about 8000:1 to about 100:1 and most preferablyfrom about 4000:1 to about 300:1.

The presently disclosed delivery agent compounds facilitate the deliveryof glucagon components (e.g. glucagon) particularly in oral, intranasal,sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal,vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral,intraperitoneal, intravenous, intramuscular and ocular systems, as wellas traversing the blood-brain barrier. The compositions and dosage unitforms of the present invention may be administered by any of theaforementioned routes.

In one embodiment of the present invention, the compositions and dosageunit forms of the present invention, when administered orally orintraorally to a human, achieve therapeutic levels of glucagoncomparable to that obtained via parental, subcutaneous, or intravenousadministration of glucagon (when administered without a delivery agent).

Without being bound by any particular theory, applicants believe thatwhen the compositions of the present invention are administeredintraorally, there is less dilution and fewer food effects, as comparedto oral administration. Intraorally administration can also provide arapid release of glucagon so as to rapidly reverse depressed serumglucose levels in patients. Alternatively, intraoral administration canalso provide a sustained (flat) release profile, which is helpful, forexample, to maintain a suitable serum glucose level over a longer timeperiod.

Dosage unit forms can also include any one or combination of excipients,diluents, disintegrants, lubricants, plasticizers, colorants,flavorants, taste-masking agents, sugars, sweeteners, salts, and dosingvehicles, including, but not limited to, water, 1,2-propane diol,ethanol, olive oil, or any combination thereof.

Dosage unit forms for introral administration may contain ingredientsknown to facilitate introral administration. The intraoral dosage unitform, for example, may be formulated so as to erode gradually over apredetermined time period and release the glucagon and delivery agent ata constant or substantially constant rate. According to one embodiment,the time period ranges from about 0.5 hours to about 24 hours. Abioerodible (hydrolyzable) polymeric carrier that adheres the dosageform to the intraoral mucosa, such as that described in U.S. PublishedPatent Application No. 2003/0134861 (which is hereby incorporated byreference), can be used, e.g., to provide a sustained release profile.Suitable bioerodible (hydrolyzable) polymeric carriers include, but arenot limited to, those which provide a sustained release profile and arecompatible with the glucagon and delivery agent. According to oneembodiment, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Non-limiting examples of polymeric carriers useful hereininclude acrylic acid polymers, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich is one suchpolymer). Other suitable polymers include, but are not limited to:hydrolyzed polyvinylalcohol; polyethylene oxides (e.g., Sentry Polyox®water soluble resins, available from Union Carbide of Midland, Mich.);polyacrylates (e.g., Gantrez®, which may be obtained from GAF of Wayne,N.J.); vinyl polymers and copolymers; polyvinylpyrrolidone; dextran;guar gum; pectins; starches; and cellulosic polymers such ashydroxypropyl methylcellulose (e.g., Methocel®, which may be obtainedfrom the Dow Chemical Company of Midland, Mich.), hydroxypropylcellulose (e.g., Klucel®, which may also be obtained from Dow),hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285 whichis incorporated by reference), hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, methyl cellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate butyrate, andthe like.

Other components may also be incorporated into the introral dosage formsdescribed herein. The additional components include, but are not limitedto, disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. Non-limiting examples of disintegrants aremanitol, sodium starch gyycolate, cross-linked polyvinylpyrrolidones,such as crospovidone (e.g., Polyplasdone® XL, which may be obtained fromGAF), cross-linked carboxylic methylcelluloses, such as croscarmelose(e.g., Ac-di-sol®, which may be obtained from FMC Corporation ofPhiladelphia, Pa.), alginic acid, and sodium carboxymethyl starches(e.g., Explotab®, which may be obtained from Edward Medell Co., Inc.),methylcellulose, agar bentonite and alginic acid. Suitable diluentsinclude, but are not limited to, those which are generally useful inpharmaceutical formulations prepared using compression techniques, e.g.,dicalcium phosphate dihydrate (e.g., Di-Tab®, which may be obtained fromStauffer), sugars that have been processed by cocrystallization withdextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pakg,which may be obtained from Amstar), lactone, calcium phosphate,cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugarand the like. Suitable binders include, but are not limited to, thosethat enhance adhesion. Non-limiting examples of such binders are starch,gelatin and sugars such as sucrose, dextrose, molasses, and lactose.Non-limiting examples of lubricants include, but are not limited to,stearates (e.g., magnesium stearate) and stearic acid.

In a preferred embodiment, the glucagon and delivery agent areformulated with a starch to form a tablet or film. Amounts of starch tobe added to the formulation can be determined by persons of ordinaryskill in the art, and include, for example, 1 wt %, 2.5 wt %, 5 wt %,7.5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt % or 60 wt % ofstarch, based on the total weight of the formulation.

Preferred intraoral dosage forms include sublingual tablets, creams,ointments and pastes. The tablet, cream, ointment or paste forsublingual delivery comprises a therapeutically effective amount ofglucagon and one or more conventional nontoxic carriers suitable forintraoral (e.g., sublingual) drug administration. The intraoral dosageforms of the present invention can be manufactured using conventionalprocesses. The intraoral dosage unit is fabricated to disintegraterapidly. The time period for complete disintegration of the dosage unitis typically in the range of from about 10 seconds to about 30 minutes,and optimally is less than 5 minutes.

Other components may also be incorporated into the intraoral dosageforms described herein. The additional components include, but are notlimited to, binders, disintegrators, wetting agents, lubricants, and thelike. Examples of binders that may be used include water, ethanol,polyvinyl pyrrolidone, and starch solution gelatin solution. Suitabledisintegrators include, but are not limited to, dry starch, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, and lactose. Wetting agents, if used,include glycerin, and starches. Suitable lubricants include but are notlimited to, stearates and polyethylene glycol. Additional componentsthat may be incorporated into intraoral dosage forms include those knownin the art; including those described in Remington's, The Science andPractice of Pharmacy, (Gennaro, A. R., ed., 20th edition, 2003, MackPub. Co.) which is herein incorporated by reference.

One or more of a solvent, an optional cosolvent, a hydrogel, and an oralmucosal membrane transport enhancing agent, including those described inU.S. Pat. No. 5,284,657 (which is hereby incorporated by reference), maybe included in a dosage unit form for, for example, intraoral or oraladministration. The solvent may comprise from about 50 percent w/v toabout 95 percent w/v or from about 55 percent w/v to about 80 percentw/v of a carrier of a non-toxic alcohol. Suitable non-toxic alcoholsinclude, but are not limited to, ethanol, isopropanol, stearyl alcohol,propylene glycol, and polyethylene glycol (e.g., those having amolecular weight of up to about 650 daltons). Non-toxic alcohols for usein pharmaceutical formulations are well known in the art (cf., forexample, Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and The Pharmaceutical Society ofGreat Britain (1986), which is hereby incorporated by reference in itsentirety).

The cosolvent may be selected from water or a pharmaceuticallyacceptable oil. Suitable oils for use in the unit dosage form of thisinvention include mineral oil, Neobee™ oil, olive oil, sunflower oil,corn oil, peanut oil and the like. Hydrogels suitable for use in thedosage unit form include hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC), polyacrylic acid, andpoly(methyl methacrylic acid).

Typically, the oral mucosal membrane transport enhancing agentfacilitates the absorption of the therapeutic agent (e.g., glucagon)across the mucosal tissues in the oral cavity and directly into theblood stream of the subject. Suitable tissue transport enhancing agentsinclude, but are not limited to, pharmaceutically acceptable andnon-toxic essential oils, volatile oils, inorganic acids, and organicacids.

Essential or volatile oils which may be employed in the compositionsinclude, but are not limited to, peppermint oil, spearmint oil, menthol,pepper oil, eucalyptus oil, cinnamon oil, ginger oil, fennel oil, anddill oil. The essential or volatile oil, when employed as the oralmucosal membrane transport enhancing agent in the dosage unit form maybe present in a concentration ranging between about 0.5 percent w/v andabout 50 percent w/v of the carrier.

Suitable inorganic and organic acids include, but are not limited to,hydrochloric acid, phosphoric acid, aromatic and aliphaticmonocarboxylic or dicarboxylic acids of from two to thirty carbon atomssuch as acetic acid, citric acid, lactic acid, oleic acid, linoleicacid, lauric acid, plamitic acid, benzoic acid, and salicylic acid. Asused in this paragraph, the term “aromatic” carboxylic acid refers toany acid which contains the 6-membered carbocyclic ring systemcharacteristic of benzene, and the term “aliphatic” carboxylic acidrefers to any acid which contains a straight-chain or branched chainsaturated or unsaturated hydrocarbon backbone.

Liquid compositions for intraoral administration can be formulated intoa liquid spray, a liquid drop, a gel or a paste. The desired consistencycan be achieved by including in the liquid composition one or morehydrogels, substances that absorb water and produce gels of varyingviscosity. Hydrogels suitable for use in pharmaceutical preparationsinclude those known well known in the art, including those described inHandbook of Pharmaceutical Excipients, supra, and Handbook ofWater-Soluble Gums and Resins, ed. by R. L. Davidson, McGraw-Hill BookCo., New York, N.Y. (1980) (both of which are hereby incorporated byreference).

Suitable hydrogels for use in the compositions of this invention includehydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethyl cellulose, polyacrylic acid, poly(methyl methacrylic acid)(PMMA). Preferred hydrogels are cellulose ethers such ashydroxyalkylcellulose (e.g., hydroxypropyl cellulose) andhydroxyalkylalkyl-cellulose compounds. Hydroxypropyl cellulose iscommercially available in a wide range of viscosity grades sold underthe tradename Klucel™ (Hercules, Ltd., London, England). Theconcentration of the hydroxyalkylcellulose is dependent upon theparticular viscosity grade used and the desired viscosity of the liquidcomposition. For example, where the desired viscosity is less than about1000 centipoise (cps), hydroxypropyl cellulose having an averagemolecular weight of about 60,000 daltons (i.e., Klucel EF™) can be used.Where the desired viscosity is from about 1000 to about 2500 cps, higherviscosity grades of hydroxypropyl cellulose can be used (e.g., KlucelLF™ and Lucel GF™).

The dosage unit form for intraoral administration may also includecollagen, a water soluble additive, and/or other pharmaceuticaladditives, such as those described in U.S. Pat. No. 5,496,559, which ishereby incorporated by reference. Collagen includes, for example,atelocollagen which is derived from a natural resource, and which isfree of a telopeptide which is an antigenic portion of collagen;chemically modified atelocollagen; and naturally-occurring collagen. Thecollagen which has been chemically derived from the atelocollagenincludes, for example, a succinylated collagen and a methylatedcollagen. The naturally-occurring collagen includes, for example, acollagen from a skin of bovine, a chorda of bovine, a bowel of porcineand sheep, and a human placenta. The collagen can contain a buffer, suchas phosphate buffer, citrate buffer, and acetate buffer, and/or astabilizer. Water soluble additives include for example, proteins,glycoproteins, amino acids, polyamino acids, peptides, saccharides,water-soluble polysaccharides, or a combination thereof. Proteinsinclude, for example, gelatin and albumin. Glycoproteins include, forexample, globulin. Amino acids include, for example, aspartic acid,arginine, glycine, and leucine. Polyamino acids and peptides include,for example, polyalanine, polyglycine, sodium polygultamate, sodiumpolyaspartate, polylysine, and polyleucine. Saccharides,polysaccharides, and water-soluble polysaccharides include, for example,fructose, sucrose, lactose, dextran, cyciodextran, mannitol, andsorbitol. A stabilizer includes one which is used for the proteinaceousphysiologically active substances, such as albumin, gelatin, mannitol,and trehalose. Suitable preservatives include, but are not limited to,p-hydroxybenzoates, sorbic acid, and salicylic acid. Suitable buffersinclude, but are not limited to, citrate buffer, acetate buffer, andphosphate buffer. Suitable sweeteners include, but are not limited to,mannitol, glucose, maltose, starch, and lactose. Suitable flavorsinclude, but are not limited to, aspartic acid, citric acid, and lacticacid. Suitable binder include, but are not limited to, methylcellulose,ethylcellulose, and carboxy methyl cellulose. Suitable suspending agentsinclude, but are not limited to, Tween 20 and Tween 80. Suitabledisintegrators include, but are not limited to, glycerol and starch.

Dosage unit forms for intraoral administration may be in the form of ahard candy (e.g. lollipops and mints) or a film, e.g., a slow dissolvingfilm or a fast dissolving film (such as that described in U.S. Pat. No.6,596,298, which is hereby incorporated by reference). Such films can beprepared by including a film forming agent in the dosage unit form.Suitable film forming agents include, but are not limited to, thosedescribed in U.S. Pat. No. 6,596,298 (e.g., pullulan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinylalcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanthgum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl polymer, amylose, highamylose starch, hydroxypropylated high amylose starch, dextrin, pectin,chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soyprotein isolate, whey protein isolate, casein and mixtures thereof.According to one embodiment, the concentration of film forming agent inthe dosage unit form ranges from about 0.01 to about 99 wt %, from about30 to about 80 wt %, from about 45 to about 70 wt %, or from about 60 toabout 65 wt % (based upon 100% total weight of the film). Administrationcompositions can also take the form of a pouch that can be placed nextto the cheek, or between the lower teeth and lip, similar to smoke-lesstobacco products.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animals,including but not limited to birds such as chickens; fish, reptiles,insects, mammals, such as rodents, cows, pigs, dogs, cats, primates, andparticularly humans.

EXAMPLES

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated.

Example 1 Aqueous Gel Formulation of a Sublingual Dosage Form

0.5 mL of glucagon powder was dissolved 0.5 mL of deionized water. 50 mgof SNAC powder was added to the glucagon solution until the SNAC wascompletely dissolved. 10 mg of Klucel powder was slowly added into theabove Glucagon/SNAC solution to form a uniform aqueous gel forsublingual dosing.

Example 2 Intraoral Delivery of Glucagon in Beagles IntraorallyAdministered Tablet and Aqueous Gel Formulation

An aqueous gel formulation of glucagon, SNAC and Klucel in water wasprepared by combining 1 mg glucagon, 100 mg SNAC, 3 mg Klucel BF and 0.5mL DI water per 10 kg weight of dog by the general procedure describedin Example 1.

A sublingual tablet was prepared with 1 mg of glucagon solid powderwhich was gradually added and blended with about 100 mg Delivery Agent(SNAC) per 10 kg weight of dog model. Upper punch, lower punch and dieof Carver 4350 manual pellet press with a Caplet shape model sold byNatoli Engineering Company, Inc. were treated with manitol. About 101 mgof mixed powder was fed into the die and a mini bead shape tablet wasmade at about 1000 PSI. The resulting solid dosage form was about 5 mmdiameter and about 1 mm in height.

The solid dosage form was placed under one dog's tongue and the aqueousgel was used under the other dog's tongue. To facilitate the dissolutionof the tablet, about 0.75 ml of saline solution was infused slowly underthe tongue on the right side and another 0.75 ml on the left side. Onehour post-administration, any remaining formulation was removed bysyringe aspiration and the sublingual area was rinsed once with salinesolution, removing it afterwards by syringe aspiration.

Two male Beagle dogs weighing between 10.2 and 12.7 kg were fastedovernight before the experiments. The animals were moderately sedatedusing 0.4-0.8 mg/kg midazolam and 0.03-0.04 mg/kg medetomidine. Oncesedated, an intravenous catheter was placed on the cephalic vein forblood sampling.

The aqueous gel dosage form was placed under the dog's tongue and thetablet under the other dog's tongue. One hour post-administration, anyremaining formulation was removed by syringe aspiration and thesublingual area was rinsed once with saline solution, removing itafterwards by syringe aspiration.

Blood samples (about 0.5 ml) were collected serially from the cephalicvein, typically at time=0 (predose), 15, 30, 45, 60, 90, 120, 150, and180 minutes post dose. The samples were placed in serum separating tubesand left at room temperature for 30-45 minutes to allow clotting. Thesamples were then centrifuged at about 2-8° C. for 10 minutes at 2500rpm. The resulting serum was transferred into a tube and placed on dryice and then stored frozen at −70±10° C. until assayed. Results from theanimals in each group were averaged for each time point. The results (±standard error) are shown in FIG. 1.

A separate study was performed based on sublingual administration of anaqueous gel dosage form of 0.3 mg. of glucagon and 100 mg of SNAC,prepared as described in Example 1, to a group of 4 beagles (referred inTable 1 as “0.3/100 gel”). The results are shown in FIG. 8.

Example 3 Intraoral Delivery of Glucagon in Beagle Does SublingualTablet and Intramuscular Glucagon as a Control

A sublingual tablet was prepared with 1 mg of glucagon solid powderwhich was gradually added and blended with about 20 mg manitol per 10 kgweight of dog model. Upper punch, lower punch and die of Carver 4350manual pellet press with a Caplet shape model sold by Natoli EngineeringCompany, Inc. were treated with manitol. About 101 mg of mixed powderwas fed into the die and a mini bead shape tablet was made at about 1000PSI. The resulting solid dosage form was about 5 mm diameter and about 1mm in height.

Two male Beagle dogs weighing between 10.2 and 12.7 kg were fastedovernight before the experiments. The animals were moderately sedatedusing 0.4-0.8 mg/kg midazolam and 0.03-0.04 mg/kg medetomidine. Oncesedated, an intravenous catheter was placed on the cephalic vein forblood sampling.

The solid dosage form was placed under one dog's tongue. To facilitatethe dissolution of the tablet, about 0.75 ml of saline solution wasinfused slowly under the tongue on the right side and another 0.75 ml onthe left side. One hour post-administration, any remaining formulationwas removed by syringe aspiration and the sublingual area was rinsedonce with saline solution, removing it afterwards by syringe aspiration.

The second dog received an intramuscular injection of glucagon 0.15 mgwhich was prepared by diluting a 0.1 mg solution of glucagon with DIwater (0.1 ml) per 10 kg weight of dog to act as a positive control.

Blood samples (about 0.5 ml) were collected serially from the cephalicvein, typically at time=0 (predose), 15, 30, 45, 60, 90, 120, 150, and180 minutes post dose. The samples were placed in serum separating tubesand left at room temperature for 30-45 minutes to allow clotting. Thesamples were then centrifuged at about 2-8° C. for 10 minutes at 2500rpm. The resulting serum was transferred into a tube and placed on dryice and then stored frozen at −70±10° C. until assayed. Results from theanimals in each group were averaged for each time point. The results areshown in FIG. 2.

Example 4 Intraoral Delivery of Glucagon in a Beagle Dog

A sublingual tablet was prepared with 0.3 mg of glucagon solid powderwhich was gradually added and blended with about 30 mg SNAC per 10 kgweight of beagle. Upper punch, lower punch and die of Carver 4350 manualpellet press with a Caplet shape model sold by Natoli EngineeringCompany, Inc. were treated with mannitol. About 101 mg of mixed powderwas fed into the die and a mini bead shape tablet was made at about 1000PSI. The resulting solid dosage form was about 5 mm diameter and about 1mm in height.

Two male Beagle dogs weighing between 10.2 and 12.7 kg were fastedovernight before the experiments. The animals were moderately sedatedusing 0.4-0.8 mg/kg midazolam and 0.03-0.04 mg/kg medetomidine. Oncesedated, an intravenous catheter was placed on the cephalic vein forblood sampling.

The solid dosage form was placed under one dog's tongue. To facilitatethe dissolution of the tablet, about 0.75 ml of saline solution wasinfused slowly under the tongue on the right side and another 0.75 ml onthe left side. One hour post-administration, any remaining formulationwas removed by syringe aspiration and the sublingual area was rinsedonce with saline solution, removing it afterwards by syringe aspiration.

The second dog received an intramuscular injection of glucagon 0.15 mgwhich was prepared by diluting a 0.1 mg solution of glucagon with DIwater (0.1 ml) per 10 kg weight of dog to act as a positive control.

Blood samples (about 0.5 ml) were collected serially from the cephalicvein, typically at time=0 (predose), 15, 30, 45, 60, 90, 120, 150, and180 minutes post dose. The samples were placed in serum separating tubesand left at room temperature for 30-45 minutes to allow clotting. Thesamples were then centrifuged at about 2-8° C. for 10 minutes at 2500rpm. The resulting serum was transferred into a tube and placed on dryice and then stored frozen at −70±10° C. until assayed. Results from thebeagle receiving the sublingual tablet are shown in FIG. 3.

Example 5 Dose Optimization Study

Sublingual tablets prepared as in Example 4 were prepared with thefollowing dosage amounts: (a) 0.2 mg glucagon/20 mg of SNAC, (b) 0.3 mgglucagon/30 mg of SNAC, and (c) 1 mg glucagon/100 mg of SNAC. (The firsttwo dosage forms are respectively referred to below in Table 1 as“0.2/20 blend” and “0.3/30 blend”.) Each dosage was administered to agroup of four beagles (preceded and followed by a washout period).

The results of the dose optimization study for one of the beagels(denoted dog #3) are shown in FIG. 4. The results for the 0.2 mgglucagon/20 mg of SNAC, and 0.3 mg glucagon/30 mg of SNAC dosages forfour beagels (including dog #3) are shown in FIG. 5.

Example 6 Material Preparation Study

Three dosage forms of 0.2 mg of glucagon and 20 mg of SNAC were preparedby three different techniques and each was each administered to a groupof four beagles preceded and followed by a wash-out period. The firstdosage form was prepared by physically blending and tableting theglucagon and SNAC as described in Example 4 (referred in Table 1 belowas “0.2/20 blend”). The second dosage form was prepared by dissolving0.2 mg. of glucagon and 20 mg of SNAC in 0.5 ml of deionized water insmall lyophilization bottle and lyophilizing for 48 hours and thentableting the lyophilized powder (referred to in Table 1 below as“0.2/20 lyophilzation”). The third dosage form was prepared bydissolving 0.2 mg. of glucagon and 20 mg of SNAC in 0.5 ml of deionizedwater and air-drying, and tableting the solid obtained from air-drying(referred to in Table 1 below as “0.2/20 air-dried”). The results areshown in FIG. 6.

A fourth dosage form was prepared by tableting a blend of 0.2 mg ofglucagon, 20 mg of SNAC, with starch as an excipient (referred to inTable 1 below as “0.2/20 starch”). The results when administered to agroup of four beagles is shown in FIG. 7.

A brief summary of the results of various formulations described aboveis shown below in Table 1:

TABLE 1 Dosage Form mean ± SD (n = 4) Tmax (min) CV 0.3/30 blend 209.25± 31   60 14.81 0.2/20 blend 159.75 ± 33.75 60 20.97 0.2/20 air-dried190.5 ± 3.53 80 1.86 0.2/20 lyophilization 218.25 ± 27.18 80 12.450.2/20 starch  245.5 ± 36.83 90 15 0.3/100 gel 232.25 ± 60.62 90 26.1

Any information regarding specific mechanism(s) is provided for onlybackground purposes. The invention should not be construed to belimited, in any way, by any description of the mechanism(s) by which thedelivery agents or active agents (e.g., glucagon, glucagon agonists) mayfunction.

The above-mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed description. Allsuch obvious variations are within the fully intended scope of theappended claims.

We claim:
 1. A dosage unit form comprising (a) glucagon, and (b) adelivery agent of the formula

and salts thereof, wherein: Ar is 2-hydroxyphenyl or 2-hydroxynaphthyl;Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; R⁷ is selectedfrom C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl)phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₂-C₁₀alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ alkenyl),naphthyl(C₁ -C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl); R⁸ is selectedfrom hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy; R⁷ is optionally substituted with C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹, or anycombination thereof; R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; andR⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof, wherein the dosage unit form is suitable forintraoral administration.
 2. The dosage unit form of claim 1, whereinthe delivery agent is selected from the group consisting of themonosodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, themonosodium salt of N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, themonosodium salt of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, themonosodium salt of 8-(2,6-dihydroxybenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-bromobenzoylamino)octanoic acid, themonosodium salt 8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-iodobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-methylbenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid, thedisodium salt of N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, thedisodium salt of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, andthe disodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid.3. The dosage unit form of claim 1 wherein the delivery agent isN-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceuticallyacceptable salt thereof.
 4. The dosage unit form of claim 1 wherein thedelivery agent is N-(10-[2-hydroxybenzoyl]-amino)decanoic acid or apharmaceutically acceptable salt thereof.
 5. A dosage unit formcomprising: (A) the dosage unit form of claim 1; and (B) (a) anexcipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) aplasticizer, (f) a colorant, (g) a dosing vehicle, or (h) anycombination thereof.
 6. The dosage unit form of claim 5, wherein thedosage unit form is in the form of a tablet, a capsule, a particle, apowder, a sachet, or a liquid.
 7. The dosage unit form of claim 6,wherein the dosing vehicle is a liquid selected from the groupconsisting of water, aqueous propylene glycol, phosphate buffer,1,2-propane diol, ethanol, and any combination thereof.
 8. A method foradministering an effective amount of glucagon to a patient in needthereof, comprising the step of intraorally administering the dosageunit form according to claim
 1. 9. A method of treating hypoglycemia ina patient in need thereof, comprising the step of intraorallyadministering to the patient an effective amount of the dosage unit formaccording to claim
 1. 10. A method of preparing a dosage unit formcomprising the step of mixing (a) glucagon, and (b) a delivery agent ofthe formula

or a salt thereof, wherein: Ar is 2-hydroxyphenyl or 2-hydroxynaphthyl;Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; R⁷ is selectedfrom C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl)phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₂-C₁₀alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl); R⁸ is selected fromhydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy; R⁷ is optionally substituted with C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹, or anycombination thereof; R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; andR⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof, wherein the dosage unit form is suitable forintraoral administration.
 11. The dosage unit form according to claim 1containing at least about 0.1 mg to about 1 mg of glucagon with at leastabout 30 mg to about 100 mg of carrier.
 12. A dosage unit formcomprising (a) glucagon, and (b) a delivery agent of the formula

and salts thereof, wherein: Ar is 2-hydroxyphenyl or 2-hydroxynaphthyl;Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; R⁷ is selectedfrom C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl)phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₂-C₁₀alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl); R⁸ is selected fromhydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy; R⁷ is optionally substituted with C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, and —CO₂R⁹ , or anycombination thereof; R⁹ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; andR⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof, wherein the dosage unit form is suitable forsublingual administration.
 13. The dosage unit form of claim 12, whereinthe delivery agent is selected from the group consisting of themonosodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, themonosodium salt of N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, themonosodium salt of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, themonosodium salt of 8-(2,6-dihydroxybenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-bromobenzoylamino)octanoic acid, themonosodium salt 8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-iodobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-methylbenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid, themonosodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid, thedisodium salt of N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, thedisodium salt of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, andthe disodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid.14. The dosage unit form of claim 12, wherein the delivery agent isN-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceuticallyacceptable salt thereof.
 15. The dosage unit form of claim 12, whereinthe delivery agent is N-(10-[2-hydroxybenzoyl]-amino)decanoic acid or apharmaceutically acceptable salt thereof.
 16. A method of treatinghypoglycemia in a patient in need thereof, comprising the step ofsublingually administering to the patient an effective amount of thedosage unit form according to claim
 12. 17. The dosage unit form ofclaim 1, wherein the weight ratio of glucagon to delivery agent is about1:100.
 18. The dosage unit form of claim 12, wherein the weight ratio ofglucagon to delivery agent is about 1:100.